The saliva of every blood-sucking arthropod vector for disease (diseases that range from malaria and leishmaniasis to Lyme disease) that has been examined thus far has been found to contain extremely potent molecules that have either pharmacological or immunosuppressive being found to also enhance their infectivity of the pathogens that theses vectors transmit. The saliva of the sand fly (the vector for leishmania) dramatically augments infection with Leishmania in mice and can determine whether Leishmania is able to successfully establish infection in the host. Therefore, it may be possible to vaccinate humans against these various diseases by vaccinating against the molecules in vector saliva that allow the pathogen to establish infection in the host. This application seeks to identify the factors in saliva that enhance infection in the host and to determine whether vaccination with these molecules will make the host resistant to infection with the pathogen when it is transmitted to the host by the relevant vector. A gene that codes for one protein confers significant protection against a challenge with a mixture of sand fly saliva plus Leishmania. Since vector saliva clearly plays an important role in disease transmission and pathology, the work will also dissect the mechanisms underlying the immunosuppressive effects of saliva. Sand fly saliva inhibits several important functions of macrophage: the ability to present antigen and to produce H202 and nitric oxide. Therefore, the mechanisms responsible for these observations will be analyzed. Lyme disease is rapidly becoming a serious health problem in the United States. Recent experiments demonstrated that there is an extremely potent immunosuppressive protein in the saliva of the tick vector for Lyme disease, Ixodes domini. We will clone the gene that codes for this protein and determine whether its product enhances infection with the ethnological agent of Lyme disease, Borrelia burgdorferi.